Clinical Information

Ravulizumab (Ultomiris, Alexion Pharmaceuticals) is a humanized monoclonal IgG2/4 kappa antibody therapeutic directed against the complement component 5 (C5). By association with C5, ravulizumab inhibits the terminal complement pathway through simultaneous blockade of the generation of the potent prothrombotic and proinflammatory molecule, C5a, and the formation of membrane attack complex initiator, C5b. Since ravulizumab demonstrated noninferiority to eculizumab in clinical trials for both paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome (aHUS), there is likelihood of patients being moved from eculizumab to ravulizumab therapy. Ravulizumab is a longer-acting hybrid IgG2/IgG4 therapeutic monoclonal antibody (145 kDa). Its sequence is very similar to eculizumab (148 kDa), except for a 4 amino acid difference in the heavy chain of the molecule. Eculizumab binds to C5 in the intravascular space and, after the resulting eculizumab-C5 complex is taken up by endothelial cells, it is degraded in the endosomes. In order to increase its half-life, two changes were made to ravulizumab: 2 amino acids substituted in the constant region give ravulizumab more affinity for the Brambell receptor (FcRn), which recycles IgG instead of degrading it. The other 2 amino acid changes are in the variable region of the heavy chain, changing the affinity of the Fab fraction for C5, making it possible for C5 to be released from ravulizumab before it is recycled, so that C5 is left alone inside the endosome to be degraded.

Eculizumab is administered as a standard (non-weight based) dose for approved conditions. Ravulizumab's key improvements over eculizumab include a longer half-life, leading to intravenous infusions every 8 weeks instead of every 2 weeks, along with a weight-based dosing schedule that further personalizes therapy regimens. Some patients who persist with serum concentrations above therapeutic targets with complete complement blockade could benefit from dose deescalation or prolonged infusion intervals and visit the clinic for infusions less frequently than the US Food and Drug Administration-label recommendation. Therapeutic drug monitoring of ravulizumab could result in cost-savings and improved quality of life if target therapeutic concentrations can be achieved with complete complement system blockage at less frequent dosing intervals.

Ravulizumab trough therapeutic concentration is greater than 175 mcg/mL Complement blockage studies can aid in determining that a therapeutic concentration of the drug has blocked the complement function and subsequent production of sC5b-9. The recommended test for complement blockage evaluation in ravulizumab therapy is the alternative pathway function assay; see AH50 / Alternative Complement Pathway, Functional, Serum. A panel with both ravulizumab concentration and alternative pathway function  is available; see RAVMP / Ravulizumab Monitoring Panel, Serum.